Major depressive disorder is accompanied by dysfunctional cognitive and neuroendocrine processing of stressful information. The neurocircuitry underlying aberrant stress processing remains to be elucidated. Human imaging data and rodent stress studies suggest that limbic cortical regions are well-positioned to mediate hypothalamic-pituitary-adrenocortical (HPA) axis pathology seen in depression. The current proposal uses a functional/anatomical approach to test the hypothesis that limbic cortical regions, including the prelimbic and infralimbic cortices, use separate yet complementary mechanisms to integrate psychological and physiological stimuli into appropriate stress responses. The neuroendocrine and mood changes seen in depression likely reflect a failure of these cortical regions to appropriately interpret relevant stressful stimuli. This hypothesis will be tested in four Specific Aims. Aim 1 will use anatomical approaches to delineate monosynaptic and multisynaptic neural pathways connecting limbic cortices with hypothalamic stress effectors. Aim 2 will use neurocircuit targeting approaches to test the necessity and sufficiency of defined limbic cortical subregions in inhibiting responses to psychological vs. physiological stressors. Aim 3 tests the involvement of specific limbic cortical-hypothalamic and limbic cortical-hippocampal circuits in mediating responses to stress, using a targeted intervention design. Finally, Aim 4 tests for interactions between limbic cortices and other limbic stress-regulatory regions, to determine whether limbic stress integration involves convergent projections or separate ?labeled lines? to the hypothalamus. These studies are expected to identify limbic cortical circuits and mechanisms involved in stress integration, and thereby provide clear neuroanatomical targets for development of improved behavioral/pharmacological interventions for depression and other stress-related disease states.